Two aspects of lipid metabolism that are affected in diabetes mellitus are under investigation: hormonal control of adipose tissue metabolism with emphasis on the effects of insulin; metabolism of lipoproteins by cultured cells (aortic smooth muscle cells and aortic endothelial cells). Further purification of hormone-sensitive lipase (HSL) is directed ultimately at defining the site phosphorylated when HSL is activated by cyclic AMP-dependent protein kinase and ascertaining the molecular changes accompanying activation. Deactivation of HSL has been shown to be due to a protein phosphatase; hormonal and substrate effects on the activity of this enzyme are under study and attempts are being made to purify it. The concurrent regulation of HSL, glycogen synthase and phosphorylase in this tissue will be further studied, particularly with regard to the role of protein phosphatases in hormonal control. Uptake and degradation of very low density, low density and high density lipoproteins by arterial endothelial cells will be studied and the effects of hormonal and substrate perturbations occurring in diabetes will be explored. Similar studies will be done with arterial smooth muscle cells with emphasis on effects on cholesterol esterase activity. The long-term goal of these studies is to gain insight as to why diabetics have premature atherosclerosis even when plasma lipoprotein levels are normal.